The American Epilepsy Society (AES) held its annual meeting on December 3-7, 2021. This was my first time attending the conference in person, as last year the event was only held virtually. I was really impacted by the vast amount of research focused on Dravet syndrome. For a rare disease, it is not mentioned rarely within these circles. While there is much to be thankful for with the ever increasing body of research into Dravet syndrome and potential treatments, there is still much that remains unknown and a true urgency to reach a place where disease-modifying treatments are a reality for patients and their families. In today’s blog post, I’ve hit some of the highlights of the topics discussed at the meeting, attempting to focus on issues I hear most commonly are of interest to the community. Below you will find sections that cover topics related to genetic-based therapies, the ketogenic diet, medications and preclinical compounds for the treatment of Dravet syndrome, special topics of interest, genetic testing, and natural history and observational studies. Please also check out my recap of this year’s DSF Research Roundtable, which took place on the evening of December 2, just prior to the AES meeting.
Genetic Therapies for Dravet Syndrome
CRISPR. Gaia Colasante, PhD spoke about a modified version of CRISPR that can be used to increase expression of the SCN1A gene, compensating for the haploinsufficiency. In this version of CRISPR, rather than cut the DNA, the Cas9 molecule is guided to a specific region of the DNA that controls the expression of the SCN1A gene where it binds and activates the gene to increase healthy copies of the encoded Nav1.1 sodium channel. It is still necessary to split the therapy into 2 vectors because the current vectors are too small to carry all of components needed, so this will still require additional preclinical work before it could be moved into a human therapy. Nevertheless, this is yet another proof-of-concept of how increasing the expression of the SCN1A gene can overcome the seizures and other symptoms of Dravet syndrome in a mouse model. Dr. Colasante also spoke about another portion of her groups work to show the potential for genetic intervention after symptom onset at the DSF Research Roundtable (reviewed here). In another session, Orrin Devinksy, MD also referenced work by other groups of academic researchers to utilize this type of CRISPR technology to overcome the SCN1A mutations that cause Dravet syndrome.
ETX101. Encoded Therapeutics has been developing a genetic therapy delivered using an adeno-associated viral (AAV) vector. ETX101 will specifically increase the productivity of the SCN1A gene using an engineered transcription factor in GABAergic inhibitory neurons in the brain, the cell-type that appears to be most affected in Dravet syndrome. They presented preclinical data from mice showing they could specifically target ETX101 to those neurons in a living animal following injection to the brain. Additionally, they showed that a single injection of ETX101 in a mouse model of Dravet syndrome on the first day of life could upregulate the SCN1A gene and increase the corresponding Nav1.1 sodium channel. Additionally, in ETX101 treated Dravet mice seizure susceptibility, frequency, and severity was reduced while survival of the mice was greatly improved. Lastly, they showed that in hon-human primates, ETX101 was broadly distributed after a single injection into the brain, without any adverse findings.
STK-001. STK-001 is an antisense oligonucleotide therapy developed by Stoke Therapeutics that works at the RNA-level to upregulate the Nav1.1 sodium channel from the healthy copy of the SCN1A gene. Lori Isom, PhD spoke about the preclinical work that showed efficacy of STK-001 to reduce seizures and mortality in a mouse model of Dravet syndrome. Stoke also presented a poster showing that the data they gathered from administration of STK-001 in non-human primates can help them to accurately model plasma and CSF levels in human patients receiving STK-001, and that these measurements can accurately predict levels of STK-001 in the brain. Using these models, Stoke predicts that 3 doses at 30mg of STK-001 given once monthly should be enough to reach pharmacologically active levels in the brain that are sustained for 3 months after the last dose.
Stoke provided follow-up interim data from their Phase 1/2a MONARCH trial of STK-001. The primary objectives of this study are to assess safety and dosing of STK-001. So far, among 22 total patients that have received either a single dose of 10mg, 20mg, or 30mg, or multiple doses of 20mg of STK-001 there have not been any serious treatment emergent adverse side effects. Concentrations of STK-001 could be detected up to 169 after treatment with a single dose, and increases after multiple doses suggest the accumulation of STK-001 in CNS tissues. Preliminary data from 17 patients showed reduction in seizures across all dose levels in patients aged 2-12 years, and in half of the patients in the 13-18 year age range. These results seem promising given the early stages of the trial, and the prediction models that suggest multiple doses at the 30mg level may be necessary to reach pharmacologically active levels. SWALLOWTAIL is an open-label extension study for patients that previously participated in studies investigating STK-001. Currently 13 patients are enrolled and receiving intrathecal doses of STK-001 every four months. No patients have discontinued treatment and there are no reported safety concerns. Stoke has also initiated a trial for STK-001 in the United Kingdom, called ADMIRAL. This trial will include 3 consecutive doses of the study drug, STK-001 (Day 1, Day 57, and Day 85). This study will be testing doses up to 70mg, higher than in the current US studies.
SCN1ANAT. Camp4 Therapeutics presented a poster on the therapeutic approach they recently acquired from OPKO. This approach uses antisense oligonucleotides (ASOs) that work at the RNA level to increase SCN1A expression in cultured cells from human patients with Dravet syndrome. They additionally show that this ASO treatment in a mouse model of Dravet syndrome can significantly reduce seizures. They are currently working on studies that will allow them to file an investigational new drug application with the FDA.
Gene Replacement. A group of researchers from Tel Aviv University are investigating the use of an adenovirus vector, which is much larger than an adeno-associated viral vector, to deliver a new copy of the SCN1A gene in a mouse model of Dravet syndrome. Their work, presented by Saja Fadila, MSc, showed that this approach could reduce seizures and premature mortality in the treated mice when given at either the onset of seizures (day 21) or after the onset of symptoms (day 35).
The Ketogenic Diet
Elaine Hsiao, PhD discussed how the ketogenic diet causes changes to the composition of the microbiome (gut bacteria) in mice. Giving mice a combination of the bacteria types that are most increased during use of the ketogenic diet can actually mimic the seizure-protection benefits of actually being on the diet in both induced-epilepsy and genetic-epilepsy mouse models. Researchers have begun to identify what the functions are of those bacteria so they may be able to directly target the pathways to mimic the presence of the ketogenic-diet associated bacteria. They were even able to correlate changes in brain chemicals to the changes they see in the gut. Greg Lum expanded on these studies by exploring microbiome transplant from human patients into mice (both before and after the ketogenic diet. Ketogenic diet-associated microbiota transplants were seizure-protective (even from patients that did not respond to keto diet in the clinic).
Lila Worden, MD spoke about a study showing that SCN1A mutation type does not predict response to ketogenic diet. Past studies have not seen strong associations between genetic mutation and response to treatments, with very similar results between missense and truncating mutations. There was no difference in this study either of the ketogenic diet between mutation types. There were some small trend towards more long-term responders to the ketogenic diet in the missense mutation group, but this would need follow-up in much larger studies to really confirm those findings (loss of function 3/17 versus missense 4/8 at 3 years of diet).
Medications for Dravet syndrome and Therapeutics in Development
UCB presented posters related to some of their newer seizure rescue options that have recently been approved or are in human clinical trials. Data from an open-label extension trial of midazolam nasal sprayhighlighted the efficacy of this option to terminate seizure cluster events, and that earlier administration during a seizure cluster event could lead to sustained control of seizures over the subsequent 24 hours. They additionally presented data that return to baseline was comparable between the use of one or two doses of midazolam nasal spray to treat seizure cluster episodes. UCB also has a new seizure medication to acutely treat predictable seizure episodes called Staccato alprazolam. Staccato is an inhaler device that aerosolizes a medication, in this case alprazolam which is a benzodiazepine that can treat seizures. Staccato alprazolam is inhaled through the mouth, with the device being activated by a normal breath. In initial clinical trials performed within a clinical setting, Staccato alprazolam use resulted in a higher percentage of patients with seizures that stopped within 2 minutes of treatment versus a placebo, with active responders trending towards a shorter time to seizure cessation following treatment. The treatment was also well tolerated and is currently beginning further human clinical trials to further evaluate the effectiveness outside of a healthcare setting.
There were several studies sponsored by Neurelis Inc. expanding on the use of diazepam nasal spray (Valtoco) as a rescue medication for seizure clusters. The safety profile remains consistent with that of diazepam rectal gel, even when a second dose is administered within 4 hours of an initial dose. They also presented on the study that is currently enrolling to assess diazepam nasal spray in children aged 2 to 5 years, which would expand the limited seizure rescue medication options for this age group, as rectal diazepam is currently the only approved option.
Another option for seizure cluster treatment is the diazepam buccal film. A study sponsored by Aquestive Therapeutics re-enforced the importance of multiple options for seizure rescue medication administration that can fit the needs of individual patients, ultimately improving quality of life.
Novel molecules that can selectively enhance the function of the Nav1.1 sodium channel are being investigated by Xenon Pharmaceuticals for the treatment of Dravet syndrome. They presented about two products, XPC-8770 and XPC-7523, that act at the Nav1.1 sodium channel and can normalize the signaling of neurons affected by SCN1A mutations in a mouse model of Dravet syndrome as well as reduce seizure susceptibility and improve motor function.
A workshop focused on the use of neuropeptides for the treatment of epilepsy discussed the potential of molecules like oxytocin (Jennifer Wong, PhD) and galanin (Cameron Metcalf, PhD) to reduce seizures and symptoms in mouse models of epilepsy. Neuropeptides can be difficult to deliver to the brain, but researchers are finding creative ways to help these molecules be delivered efficiently. For example, Dr. Wong’s group is using nanoparticles to allow oxytocin to be delivered through the nose, a method that is effective in reducing seizure susceptibility and improving behavioral tests in an SCN1A mouse model of GEFS+. These studies are all still in preclinical stages, but similar methods are being used to explore neuropeptides in human trials of autism which may pave the path for clinical trials in epilepsy.
Fenfluramine continues to show efficacy for the treatment of seizures in Dravet syndrome and data also suggests improvements beyond just seizure control for many patients. Zogenix sponsored several studies presented at AES, such as one that elucidated the improvement in executive function in preschool-aged children. Additionally, a three-year follow-up of fenfluramine use under the regular assessment of echocardiograms indicated that there are still no reports of valvular heart disease or pulmonary artery hypertension. Another important study that was presented elucidated a potential mechanism by which fenfluramine may reduce SUDEP, through its action via sigma-1 receptor signaling, as opposed to its modulation of the serotonergic system, which disrupted spreading depression of brain activity thought to be related to SUDEP risk. This is a possible mechanism behind the recent association that suggests use of fenfluramine in human patients may reduce the risk of SUDEP, although longer studies will be necessary to confirm this relationship.
A study supported by Biocodex investigated the use of stiripentol in patients with Dravet syndrome before the age of 2. A large cohort of patients in France started stiripentol before the age of 2 and side effects were quite similar to those starting the medication at older ages. Overall, the study found that the initiation of stiripentol in children younger than 2 after receiving a diagnosis of Dravet syndrome is safe and could be beneficial avoiding prolonged seizure activity.
In a translational research symposium titled “Overcoming System Barriers to Translating Research: Models of Success,” David Groppe, PhD and Ilene Penn Miller, JD, LL.M commented on the barriers to progress in better treatments for the epilepsies including the lack of large-scale collaboration and data silos. Despite the increase in our understanding of genetics, there is an under-utilization of effective diagnostics and therapies, which could be related to disparities in access to care. The mantra that “time is brain” was highlighted to emphasize that any delay in research advancements is time that patients do not have. We have to move forward with even more urgency. Chris Austin, MD, PhD noted that at the current rate of progress, it could take more than 2000 years to create unique treatments for each human condition with a molecular diagnosis, but this does not have to be the case. Advocacy can deploy multiple tactics, including emphasizing the economic burden of rare disease to regulators- a nearly 1 trillion dollar a year cost. He called for COVID-19 expediency in our acceleration of epilepsy research. Steve Roberds, MD, PhD emphasized how patient advocacy groups can be conveners to bring together stakeholders across industry, academia, and clinical settings to accelerate treatments, using the TS Alliance as an example. Overall, this symposium really drove home the need for multiple stakeholders across the epilepsies to work together to reach improved outcomes faster. Patient advocacy groups supporting common outcomes, such as through the Rare Epilepsy Network (REN) or DEE-P Connections, was emphasized as one way be stronger together with a united voice.
Ethan Goldberg, MD, PhD presented at the Presidential Symposium on several exciting research advances coming out of Children’s Hospital of Philadelphia such as using machine learning to better detect seizures. He also discussed a study done by Ingo Helbig, MD and Peter Galer, MSc by pulling out information from the Electronic Medical Record for patients with Dravet syndrome and looking for common characteristics of their medical record that could aid in clearer diagnosis. They could use this information to better predict elements that are consistent with a diagnosis of Dravet syndrome. This algorithm could make a diagnosis approximately 6-9 months earlier than the clinical diagnosis was made. It could also allow flags when a diagnosis is made that is not consistent with a patient’s electronic medical record. This exemplifies the power of utilizing patient data to improve clinical outcomes and hopefully is just a small foreshadowing of the future use of existing patient data.
Another example of use of large data sets is exemplified by a poster describing a new portal for sodium channel genes associated with epilepsy created through a large collaboration with Dennis Lal’s research group with other experts in the field. The portal coalesces information that would have previously only been sparsely available across several other disparate platforms, bringing together a “one-stop shop” research experience to investigate causal epilepsy mutations in sodium channel genes and their implications for clinical phenotypes and functional effects on the resultant sodium channel proteins. The site also brings together resources detailing the research history and includes educational videos that approachable for all audiences. Anyone can access the portal at: https://scn-portal.broadinstitute.org
Invitae’s Behind the Seizure Program has helped to make genetic testing more accessible to children under the age of 8 with unprovoked seizures through industry partnerships that help to sponsor the program and eliminate costs for patients. Despite the broader utilization of genetic testing in the current day health care system, many adults with epilepsy have never received genetic testing or a specific diagnosis. Invitae presented a poster showing that using epilepsy panels in adults is nearly as effective at informing diagnosis as in children, and the SCN1A gene is the most common positive genetic finding. Finding an SCN1A mutation that can guide diagnosis is incredibly important at any patient age, as the diagnosis of Dravet syndrome can have important implications for medication choices. Importantly, accurate diagnosis can also connect patients and their families to a community of individuals that understand their journey and can provide experience and support.
Natural History (Observational) & Related Studies
The Stoke Therapeutics-sponsored observational study, BUTTERFLY, has been collecting information from 36 patients between ages 2 and 18 years over a timeframe of up to 24 months. They have been able to appropriately assess neurodevelopment and adaptive behavior using existing measurement scales. While deficits in intellectual development and adaptive function may become greater as patients grow older, patients do retain the capacity for growth of skills. Studies like this are important for confirmation that the existing scales can accurately measure changes in patients following a treatment, as well as for furthering our understanding of the progression of Dravet syndrome.
Encoded Therapeutics presented several studies they have led towards expanding the understanding of the progression and far reaching impacts of Dravet syndrome on the patient and their family. Encoded presented data from their observational natural history study, ENVISION. This study will provide extremely important insight into the measurable endpoints that could be used to determine effectiveness of a future therapy, like ETX101. In addition, natural history studies provide valuable insight into the impact of Dravet syndrome as individuals age. The study currently includes 45 children that were enrolled between the ages of 6 months to 5 years. In this young age group, they are able to show that seizure frequency increases with age, despite the use of multiple anti-seizure medications, as well as the progression of other symptoms such as developmental stagnation by 3 years of age, delays in communication, social, and daily living skills. Motor skills are also affected as early as 3 years of age. Continuing to gather accurate data from participants in observational trials like ENVISION can help to elucidate more about the progression of Dravet syndrome and the broad effects beyond just the seizure burden. Complimentary to this natural history data, Encoded also presented a systematic literature review that drew attention to the “clinical, economic, and humanistic burden” that Dravet syndrome has on patients and their families across the entire lifetime and also exemplified the need for additional studies investigating these impacts longitudinally. Furthermore, they presented data collected in their ENGAGE caregiver study that highlighted the impacts of Dravet syndrome from the perspective of caregivers to children with Dravet syndrome under the age of 6 years. Caregivers most commonly indicated that they hoped for a therapy that could reduce seizures and stop the regression of skills. Caregivers were willing to accept invasive administration of study drugs in a clinical trial if it could improve the outcomes of Dravet syndrome. Caregivers were both optimistic about a one-time disease modifying therapy as well as cautious of a new permanent therapeutic approach. Encoded incorporated feedback from this study into development of their interventional trial for ETX101, exemplifying the importance of the patient/family-voice in the development of clinical trials.
Danielle Andrade, MD and her research group have been working on sstudies in adults with Dravet syndrome. Arunan Selvarajah, MSc presented a poster showing how even young adults with Dravet syndrome have significant deficits in their movement and gait and that parkinsonian features progress with patient age. There is a need to begin more formal assessment of gait and motor movement in patients at a young age so that this comorbidity can be better understood in Dravet syndrome and appropriate treatment plans can be developed. Another study from the same group was presented by Quratulain Zulfiqar Ali, MD, this time focused on the patient experience with adult transition of care. Unfortunately, the results indicate that access to health care professionals may decrease as patients access care in adulthood and that overall care when at clinical visits may be rated lower in the adult years. Better understanding the issues that patients are faced with during the adult transition can inform the development of further supports to each the transition to the adult health care system.
In conclusion, I hope you’ve gleaned from this blog the breadth of topics covered at AES 2021 related to Dravet syndrome. I hope you feel as inspired as I do by the way all of these researchers from various basic science, industry, and clinical backgrounds have been working to place together all of the puzzle pieces needed to reach a full understanding and treatment of Dravet syndrome. There’s still work to be done, but hope certainly remains on the horizon.